Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes

Abstract

Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

Intensity of anxiety is modified via complex integrative stress circuitries

“…Anxiety appears to be an important factor influencing BDNF expression the amygdala, as maternal anxiety impacts DNA methylation of Met/Met genotype of the BDNF Val66Met gene variant in infants and effects amygdalar volume (Chen et al, 2015). Alcohol treatment during early postnatal rat development enhances BDNF and GDNF expression in the central extended amygdala (Balaszczuk et al, 2013), and ETOH withdrawal in adult rats leads to decreased BDNF gene expression and dendritic spine density in the CeA along with increased anxious behavior (You et al, 2014).…”

Imaging structural and functional brain development in early childhood

“…Here, maternal anxiety decreased cortical thickness in neonates with two copies of the Met COMT allele but increased cortical thickness in neonates with two copies of the Val allele. BDNF genotype may also regulate the sensitivity of the methylome [G] to maternal anxiety, with differential effects on amygdala and hippocampal volume 160 . Finally, it has also recently been reported that the common variant rs17203281 in DLG4 (also known as PSD95 , which encodes postsynaptic density protein 95) is associated with significant differences white-matter microstructure (as indexed by FA) in preterm infants.…”

Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype

“…The former view that DNA methylation within the promoter region leads to gene silencing, has also been challenged recently, as more and more reports also show a positive relation between methylation and expression (Ehrlich and Lacey, 2013). Lately, the interaction between genotypes and DNA methylation has also found increased attendance, as some genotypes can affect DNA methylation throughout the whole genome (Chen et al, 2015).…”